The present invention relates to novel compounds of AA-896 which exhibit antibacterial activity.
Natural products, Liposidomycins A, B and C, have been isolated and reported to have antibacterial activity(Isono, K.; Uramoto, M.; Kusakabe, H.; Kimura, K.; Izaki, K.; Nelson, C. C.; McCloskey, J. A., J.Antibiotics, 1985, 38, 1617-1621. Ubukata, M.; Isono, K.; Kimura, K.; Nelson, C. C.; McCloskey, J. A. J.Am.Chem.Soc., 1988,110, 4416-4417. Kimura, K.; Miyata, N.; Kawanishi, G.; Kamino, Y.; Izaki, K.; Isono, K. Agric.Biol.Chem., 1989, 53,1811-1815.). Isolated Liposidomycins A-(I), A-(II), A-(III) and A-(IV) are also reported to have antibacterial activity (Kimura, K.; Ikeda, Y.; Kagami, S.; Yoshihara, M., J. Antibiotics, 1998, 51, 1099-1104. and other references herein). The detailed structural analysis of Liposidomycins A, B and C using their chemical degradation products has been reported (Ubukata, M.; Kimura, K.; Isono, K.; Nelson, C. C.; Gregson, J. M.; McClosky, J. A., J.Org.Chem., 1992, 57, 6392-6403). Liposidomycin class compounds are further reported (JPO05078385) and are derivatives of 2-methylamino-3-(5-aminomethyl-4-hydroxy-3-hydroxy-tetrahydro-fura-2-yloxy)-3-[3,4-dihyoxy-5-(2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoic acid or the degraded products of 2-methylamino-3-(5-aminomethyl-4-hydroxy-3-hydroxy-tetrahydro-fura-2-yloxy)-3-[3,4-dihyoxy-5-(2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl)tetrahydro-2-furanyl]-propanoic acid.
This invention is concerned with a new series of nucleoside peptide antibiotics of AA-896.
This invention is concerned with novel nucleoside peptide antibiotics of AA-896 which have antibacterial activity; with methods of treating infectious disease in mammals employing these novel nucleoside peptide antibiotics; with pharmaceutical compositions containing these novel nucleoside peptide antibiotics and processes for the production of novel nucleoside peptide antibiotics of the invention. Compounds according to the invention comprise compounds of the formula 
wherein:
R1 is H, aryl, alkyl (C1-C20), xe2x80x94CH2-aryl, xe2x80x94C(O)alkyl(C1-C20), C(O)NHalkyl(C1-C20), or xe2x80x94C(O)NHaryl;
R2 is H, alkyl (C1-C20), xe2x80x94CH2aryl, or xe2x80x94C(O)alkyl(C1-C20);
R3 is xe2x80x94OH;
R2 and R3 may optionally be taken together to form a moiety 
R4 is alkyl (C1-C20), or aryl;
provided R1 and R2 are not H when R3 is xe2x80x94OH
or a pharmaceutically acceptable salt thereof.
Among the preferred groups of compounds of this invention including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein other variables are as defined above:
a) R2 and R3 are taken together to form a moiety 
b) R2 is H, alkyl (C1-C12), or xe2x80x94CH2aryl; and
c) R1 is H, xe2x80x94C(O)alkyl(C1-C16), or xe2x80x94C(O)aryl when
R2 and R3 are taken together to form a moiety 
d) R4 is alkyl(C1-C16), or aryl.
Specifically preferred compounds of the invention are the following compounds or a pharmaceutically acceptable salt thereof:
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-3-(4-fluorophenyl)-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-2,4-dioxo-3-pentyl-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{((2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-3-hexyl-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-3-(4-methoxyphenyl)-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-3-dodecyl-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
16-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-15-benzyl-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-15-dodecyl-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-15-[12-(4-morpholinyl)dodecyl]-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-15-pentyl-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
4-[13-((2R)-2-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}-1-carboxy-2-{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}ethyl)-26-carboxy-19-(1-hydroxy-2-methylpropyl)-22-(2-iminohexahydro-4-pyrimidinyl)-27-methyl-18,21,24-trioxo-13,17,20,23,25-pentaazaoctacos-1-yl]-4-methylmorpholin-4-ium,
14-[5-((R)-{(2S,3S,4R,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}{[(3R,4S,5R)-4-hydroxy-3-methoxy-5-({[(octylamino)carbonyl]amino}methyl)tetrahydro-2-furanyl]oxy}methyl)-3-octyl-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{(2S,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}{[(5R)-4-hydroxy-3-methoxy-5-({[(4-fluoroanilino)carbonyl]amino}methyl)tetrahydro-2-furanyl]oxy}methyl)-3-(4-fluorophenyl)-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{(2S,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}{[(5R)-4-hydroxy-3-methoxy-5-({[(4-methoxyanilino)carbonyl]amino}methyl)tetrahydro-2-furanyl]oxy}methyl)-3-(4-methoxyphenyl)-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{(2S,3S,4R,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}{[(3R,4S,5R)-5-({[(hexylamino)carbonyl]amino}methyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}methyl)-3-hexyl-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{(2S,3S,4R,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}{[(3R,4S,5R)-5-({[(dodecylamino)carbonyl]amino}methyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}methyl)-3-dodecyl-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
16-((R)-{(2S,3S,4R,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}{[(3R,4S,5R)-5-({[(hexadecylamino)carbonyl]amino}methyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-[(R)-{(2S,3S,4R,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}({(3R,4S,5R)-4-hydroxy-3-methoxy-5-[(pentylamino)methyl]tetrahydro-2-furanyl}oxy)methyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-15-pentyl-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-[(R)-{(2S,3S,4R,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}({(3R,4S,5R)-4-hydroxy-3-methoxy-5-[(pentylamino)methyl]tetrahydro-2-furanyl}oxy)methyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-((R)-[((3R,4S,5R)-5-{[([1,1xe2x80x2-Biphenyl]-4-ylmethyl)amino]methyl}-4-hydroxy-3-methoxytetrahydro-2-furanyl)oxy]{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
15-([1,1xe2x80x2-Biphenyl]-4-ylmethyl)-16-((R)-[((3R,4S,5R)-5-{[([1,1xe2x80x2-biphenyl]-4-ylmethyl)amino]methyl}-4-hydroxy-3-methoxytetrahydro-2-furanyl)oxy]{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-((R)-({(3R,4S,5R)-5-[(Benzylamino)methyl]-4-hydroxy-3-methoxytetrahydro-2-furanyl}oxy){(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
15-Benzyl-16-((R)-({(3R,4S,5R)-5-[(benzylamino)methyl]-4-hydroxy-3-methoxytetrahydro-2-furanyl}oxy){(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid, and
16-((R)-({(3R,4S,5R)-5-[(Acetamido)methyl]-4-hydroxy-3-methoxytetrahydro-2-furanyl}oxy){(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid.
For the compounds of the invention defined above and referred to herein, unless otherwise noted, the following terms are defined:
Halogen, as used herein means fluoro, chloro, bromo and/or iodo.
Alkyl as used herein means a branched or straight chain radical having from 1 to 20 (preferably 1 to 16) or preferably (1 to 12)carbon atoms optionally substituted with morpholino where the morpholino nitrogen atom may optionally be alkylated with alkyl of 1 to 6 carbon atoms forming a quaternary salt. Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl, also optionally substituted, as well as perfluoroalkyl.
Aryl as used herein means a homocyclic or polycyclic aromatic radical, having 6 to 20 carbon atoms independently substituted with one to three substituents selected from the group of alkyl, halogen, cyano, nitro, hydroxy, , amino, alkylamino, dialkylamino, or alkoxy. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, fluorenyl, and anthracenyl, optionally substituted with one to three substituents.
The preparation of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid by fermentation is described in copending application Ser. No. 60/286,402 filed Apr. 25, 2001 incorporated herein by reference and copending application Ser. No. 60/290,156 filed May 10, 2001 incorporated herein by reference.